(P 57) CLINICAL GENOMIC PROFILING OF MALIGNANT GIANT CELL TUMOR OF BONE: A RETROSPECTIVE ANALYSIS USING A REAL-WORLD DATABASE

Objective: Malignant giant cell tumor of bone (GCTB) is identified by the presence of multinucleated giant cells, with an aggressive behavior and a high risk of metastasis, which has not been genetically characterized in detail. H3 histone family member 3A (H3F3A) gene mutations are highly recurrent and specific in GCTB. In the present study, it was hypothesized that as-yet-unknown molecular events participate in the progression of malignant GCTB.

Methods: The present study analyzed the clinical information and genomic sequencing data of eight cases of malignant GCTB (out of 384 bone sarcoma samples) using an anonymized genomic database. There were 5 males and 3 females among the cases, with a median age of 33 years at the time of the initial diagnosis.

Results: A total of 78 mutations were detected. Among these, 26 mutations were annotated as likely or known oncogenic alterations, with an average of 3.1 (26 of 8) alterations per sample. The oncoprint is depicted in Fig. 1. Single-nucleotide variants accounted for 46% (12 of 26) of the alterations, and copy number alterations (deletion and amplification) and rearrangements (fusion) accounted for 46% (12 of 26) and 8% (2 of 26), respectively. H3F3A G34W mutations (hg38, chr1: 226064454 G>T) and G34L mutation (hg38, chr1: 226064454 GG>CT) were found in 3 patients and 1 patient, respectively. In 50% of the cases with H3F3A mutation, other co-occurring mutations were related to cell cycle regulators (TP53 or RB1). mTOR pathway gene alterations (STK11 or TSC2) were detected in 3 of the 8 (38%) cases. In 75% of cases without H3F3A mutation, mitogen-activated protein kinase (MAPK) signaling pathway gene alterations were found (KRAS single nucleotide variant, KRAS amplification, NRF1-BRAF fusion). Moreover, COL1A2-ALK fusion was detected in remaining one case. The most frequent gene alterations were related to cell cycle regulators, including TP53, RB1, CDKN2A/B and CCNE1 (75%, 6 of 8 cases).

Conclusion: The findings of the present study suggest that MAPK pathway alterations are crucial in H3F3A-wild type malignant GCTB. The most frequent oncogenic event was gene alterations related to cell cycle regulators. Potentially targetable BRAF or ALK fusion may be detected in a subset of cases clinicopathologically diagnosed with malignant GCTB that lack H3F3A mutation; however, the careful validation of two fusion genes and a pathology review need to be performed. The real-world findings highlight a unique perspective on genomic alterations in clinicopathologically diagnosed malignant GCTB.